PROJECT SUMMARY/ABSTRACT There are no effective treatments for age-related dementia. Many clinical approaches investigate the late-stage symptoms, after progression of severe neurodegeneration and appearance of memory dysfunction, and seek to manage these symptoms with drugs that boost neural function. The problem with this approach is that it only begins to treat patients after severe symptoms develop (after it is too late), and it is ineffective because it does not halt the underlying progression of disease. This proposal focuses on the earliest stages of pathology that lead to later neurodegeneration. We show that aging involves decline and breakdown of the vascular blood- brain barrier, which allows blood components to begin leaking into the brain. This causes an inflammatory injury response leading to neurodegeneration and aberrant neural function. I seek to target this early mechanism, to determine if blocking this inflammatory pathway can halt or reverse cognitive decline in aging. Using aged mice and a clinically relevant small molecule drug, I treat the target pathway and assess outcomes at the level of brain structure (decrease in inflammatory signaling and neurodegeneration), brain function (electrophysiological recording to detect aberrant brain activity), and behavior (improvements in a suite of memory tasks). By focusing on the root causes of disease, these experiments seek to show the potential of a new, preventative treatment aimed at the early stages of cognitive decline in aging. The training plan includes unique approaches to prepare me for independent research, including training in translational research (bringing fundamental research innovations from the lab to clinical and industrial applications).